Drug combats complications of SCD

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Pharmaceutical-grade L-glutamine can reduce the risk of complications in patients with sickle cell disease (SCD), according to new research.

In a phase 3 study of more than 200 patients, those who received L-glutamine saw a reduction in sickle cell crises, hospitalizations, and the incidence of acute chest syndrome (ACS) when compared to patients who received placebo.

In addition, L-glutamine appeared to have a synergistic effect with hydroxyurea.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, presented these results at the 2014 ASH Annual Meeting (abstract 86*). Emmaus Medical produced the pharmaceutical-grade L-glutamine used in the study.

Dr Niihara noted that nicotinamide adenine dinucleotide (NAD) is an important physiological antioxidant in red blood cells. But in sickled red blood cells, NAD redox potential is significantly compromised.

So he and his colleagues hypothesized that glutamine, a precursor for NAD, can improve NAD redox potential and modify the destructive effect of increased oxidation and the pathophysiology of SCD. They also theorized that glutamine will decrease the frequency of vaso-occlusive crises.

To test their theories, the researchers enrolled 230 patients from 31 different sites on a phase 3 trial. Patients had sickle cell anemia (SS) or sickle B⁰ thalassemia. They were 5 years of age or older, and some were receiving hydroxyurea.

Patients were randomized 2:1 to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day) or placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks. The researchers had discovered high variation in the quality of over-the-counter L-glutamine, so they used pharmaceutical-grade L-glutamine only.

In all, 152 patients received L-glutamine, and 78 received placebo. Demographics and baseline characteristics were similar between the two treatment arms.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% and 57.7%, respectively. And most patients in both arms had sickle cell anemia—89.5% and 91%, respectively.

Safety and efficacy

Dr Niihara said there were no serious adverse events attributable to L-glutamine and no dose modifications due to toxicity.

There were more gastrointestinal events (such as constipation and flatulence) in the L-glutamine arm (8.6%) than in the placebo arm (5.2%). But there was no difference in other adverse events between the two arms.

The study’s primary endpoint was the frequency of painful sickle cell crises. Patients in the L-glutamine arm had 25% fewer crises than patients in the placebo arm (P=0.008).

In patients aged 18 and younger, the median number of sickle cell crises was 3 in the L-glutamine arm and 4 in the placebo arm (P<0.001). The numbers were the same in patients older than 18 (P<0.001) and among patients receiving hydroxyurea (P<0.001).

“Those patients, even though they were on hydroxyurea, they have shown improvements [with L-glutamine],” Dr Niihara said. “And it appears there is some synergistic effect . . ., certainly more than just an additive effect.”

Dr Niihara also noted that patients who received placebo took less than 2 months to experience a first sickle cell crisis, but, for patients on L-glutamine, it took almost 3 months before they had a first crisis. The time to a first crisis was a median of 87 days in the L-glutamine arm and 54 days in the placebo arm (P=0.010).

The study’s secondary endpoint was the frequency of hospitalizations. Compared to patients in the placebo arm, those in the L-glutamine arm had a 33% reduction in hospitalizations (P=0.005) and a 41% reduction in the length of hospital stay (P=0.022).

The researchers also looked at the incidence of ACS and found that L-glutamine was associated with a 58% reduction in ACS. The incidence was 26.9% in the placebo arm and 11.9% in the L-glutamine arm (P=0.006).

“We observed this cascade improvement [with L-glutamine],” Dr Niihara noted. “And what we mean [by that] is that, with glutamine, there is less chance of having painful crises, but if patients have to have crises, they have less chance of being hospitalized. And if they have to be hospitalized, their stays in the hospital are shorter. And, again, if they have to be hospitalized, there’s less chance of them going to the ICU with acute chest syndrome.”

Dr Niihara said the researchers’ next steps are to investigate L-glutamine in a clinical setting, in patients younger than 5 years old, in pregnant women, and as part of combination therapy.

*Information in the abstract differs from that presented at the meeting.